Combination of 5-HT7 receptor antagonist and serotonin reuptake inhibitor therapy

ABSTRACT

Patients suffering from serotonin-mediated diseases or conditions, such as depression, may be treated by administering an effective combined amount of a 5-HT7 receptor antagonist and a serotonin reuptake inhibitor.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 11/460,294, filed Jul. 27, 2006, now U.S. Pat. No. 7,598,255the disclosure of which is incorporated by reference herein, whichapplication claims priority to U.S. Provisional Application No.60/705,719, filed Aug. 4, 2005.

FIELD OF THE INVENTION

The present invention relates to methods and pharmaceutical compositionsfor treating serotonin-mediated diseases and conditions by administeringan effective combined amount of a 5-hydroxytryptamine receptor 7 (5-HT7receptor) antagonist and a serotonin reuptake inhibitor (SRI).

BACKGROUND OF THE INVENTION

The following background discussion is provided to facilitate a betterappreciation of the technology relating to the invention. As statementsin this discussion may reflect viewpoints of an inventor, they shouldnot be misconstrued as necessarily corresponding to knowledge in theprior art.

Serotonin (5-hydroxytryptamine, 5-HT) is a major neurotransmittereliciting effects via a multiplicity of receptors. To date, at leastfifteen different 5-HT receptors have been identified (Marek et al.,Neuropsychopharmacology (2003), 28:402-412), largely as the result ofcloning cDNAs, and these receptors have been grouped into seven families(5-HT1 through 5-HT7) (Hoyer et al., Pharmacol. Biochem. Behav. (2002),71:533-554). Fourteen of the fifteen cloned 5-HT receptors are expressedin the brain. Aberrant 5-HT availability or activity is implicated invarious disease states, including: certain disorders of the centralnervous system (CNS), such as depression, anxiety, schizophrenia, mooddisorders, drug and alcohol dependence and addiction disorders; sleepdisorders, jet lag, and sleep/wake disturbances; eating disorders; mooddisorders; obsessive compulsive disorder; learning and memorydysfunction; migraine; chronic pain; temperature dysregulation;nociception; neurogenic inflammation; sexual dysfunction; cardiovasculardisorders; vascular and hypertensive disorders; gastric disorders;irritable bowel disorders, urinary incontinence, hormone secretion, andcognition; and metabolic disorders. The identification of multiple 5-HTreceptors has provided an opportunity to characterize existingtherapeutic agents thought to act via the serotonergic system.

The 5-HT7 receptor is the most recently described member of the largefamily of serotonin receptors (see, e.g., Bard et al., J. Biol. Chem.(1993), 268(31):23422-23426; Hedlund et al., Trends in Pharmacol. Sci.(2004), 25(9):481-486; and Lovenberg et al., Neuron (1993), 11(3):449-458). In the rodent and human brain, the highest receptor densitieswere found in the thalamus, hypothalamus (including the suprachiasmaticnucleus), amygdala, hippocampus, cortex and dorsal raphe (Bonaventure etal., Neuroscience (2004), 124(4):901-911; Thomas et al.,Neuropharmacology (2002), 42(1):74-81; To et al., Br. J. Pharmacol.(1995), 115(1):107-116; and Varnas et al., Neurosci. Lett. (2004),367(3):313-316). The 5-HT7 receptor has also been detected in theperiphery, where it is found primarily in smooth muscle cells of bloodvessels (Bard et al., J. Biol. Chem. (1993), 268(31):23422-23426), andin the gastrointestinal tract, where it is involved in peristalsis(Tuladhar et al., Br. J. Pharmacol. (2003), 138(7):1210-1214).

Recently discovered antagonists for the 5-HT7 receptor and knockout micehave been helpful for elucidating the receptor's role in severalphysiological and pathophysiological phenomena (see, e.g., Hedlund etal., Trends in Pharmacol. Sci. (2004), 25(9):481-486 and US PatentApplication Publication No. 2005/0119295). Important functional rolesfor the 5-HT7 receptor have been established in thermoregulation,circadian rhythm, learning and memory, hippocampal signaling, sleep, andmicturition (Glass et al., J. Neurosci. (2003), 23(20):7451-7460;Guscott et al., Neuropharmacology (2003), 44 (8):1031-1037; Hagan etal., Br. J. Pharmacol. (2000), 130(3):539-548; Hedlund et al., Proc.Natl. Acad. Sci. USA (2003), 100(3):1375-1380; Meneses, A., Behav. BrainRes. (2004), 155(2):275-282; and Read et al. IUPHAR Meeting (2002), SanFrancisco, Calif., USA).

The 5-HT7 receptor is implicated in circadian rhythm phase resetting,and two selective 5-HT7 receptor-selective antagonists (SB269970 andSB656104) have been shown to induce change in sleep parameters in apattern opposite from those in patients with clinical depression. Inwild type mice, SB269970 decreased immobility in both tail suspensionand forced swim test, two tests used as predictor of antidepressantactivity (Guscott et al. (2005), Neuropharmacology, 48(4):492-502; andHedlund et al. (2005), Biol. Psychiatry, 58(10):831-837). Whenadministered at the beginning of the sleep phase, both SB269970 andSB656104 increased the latency to rapid eye movement (REM) sleep anddecreased the amount of time spent in REM sleep (Hagan et al., Br. J.Pharmacol. (2000), 130(3):539-548 and Thomas et al., Br. J. Pharmacol.(2003), 139(4):705-714). In addition, 5-HT7 knockout mice showed reducedimmobility in both the forced swim and the tail suspension tests andspent less time in and had less frequent episodes of REM sleep, alsoconsistent with an antidepressant like state (Hedlund et al., Biol.Psychiatry (2005), 58(10):831-837).

Some current treatments for depression exhibit considerable delaybetween start of treatment and subjective improvement. Many drugs do notcause an improvement in the Hamilton Rating Scale for Depression untilafter several weeks of treatment. Various drugs that are now availablehave a limited response rate and in some clinical trials only about 30%of patients show clinical improvement (Menza et al., J. Clin. Psych.(2000), 61:378-381). Psychiatrists frequently have to evaluate severaldrugs for individual patients before a satisfactory therapeutic responseis observed.

Current clinical treatment of depression typically involves a drugselected from one of four types of drugs: 1) monoamine oxidase (MAO)inhibitors; 2) tricyclic antidepressants (TCA); 3) selective serotoninreuptake inhibitors (SSRIs); and 4) other drugs such as reboxetine andvenlafaxine. MAOs have long been used as second-line drugs because oftheir potentially dangerous side effects; but more recently, reversibleMAO-A selective inhibitors with improved profiles have been described(Bonnet, CNS Drug Reviews (2002), 8:283-308). TCAs such as amitryptilinedisplay complex pharmacological activities. They inhibit reuptake ofnoradrenaline and serotonin via their respective transporters, but alsohave affinity at muscarinic and histamine H₁ receptors. Thus, theirefficacy in treating depression is counterbalanced by numerous unwantedside effects. The SSRIs, which represent a large and successful class ofantidepressants (see, e.g., Spinks, Current Med. Chem. (2002),9:799-810), show a higher selectivity for the serotonin transporter(SERT) than for the norepinephrine transporter (NET), although the exactaffinity ratio varies from drug to drug. This class of drugs istypically characterized by a milder side-effect profile than theMAO-inhibitors or the TCAs. Other drugs have been described, such asreboxetine, which preferentially targets the NET, and venlafaxine, whichhas dual activity at the SERT and NET (Olver et al., CNS Drugs (2001),15: 941-954).

Although progress has been made in the treatment of various diseases anddisorders associated with aberrant 5-HT function, there remains a desirefor improved therapies.

SUMMARY OF THE INVENTION

Recent data suggest that there is a complex interaction between 5-HT7receptors and glutamatergic neurons in the raphe nuclei that influencesthe activity of the 5-HT neurons (see, e.g., Harsing et al., Neurochem.Res. (2004), 29(8):1487-1497 and Roberts et al., Neuropharmacology(2004), 46(7), 935-941). The axon terminals of the glutamatergiccorticoraphe neurons may possess 5-HT7 receptors. Activation of these5-HT7 receptors inhibits glutamate release, which consequently leads todecreased activity of serotonergic neurons. Blockade of 5-HT7 receptorsmay lead to an increased activity of serotonergic neurons.

The administration of a 5-HT7 receptor antagonist may therefore augmenteffects achieved with administration of another serotonergic agent, suchas a selective SRI (SSRI). Indeed, experiments described herein reflectthat administration of both a 5-HT7 receptor antagonist and an SRI canyield an advantageous complementary effect useful in and in treatingserotonin-mediated diseases and conditions. Thus, the invention isdirected to general and preferred embodiments of methods andpharmaceutical compositions for treating or preventingserotonin-mediated diseases or conditions as defined herein. Additionalpreferred embodiments, features, and advantages of the invention will beapparent from the following detailed description taken in conjunctionwith the drawing figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B depict effects of administration of the indicated dosesof each of the 5-HT7 receptor antagonists,(R)-3-[2-[2-(4-methylpiperidin-1-yl)ethyl]pyrrolidine-1-sulfonyl]phenolhydrochloride (SB269970) and1-benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene(Compound A), independently on mice in the setting of the tailsuspension test (FIGS. 1A and 1B, respectively). Data bars represent themean±standard error of the mean (SEM) and n=8. In FIG. 1A, *=p<0.05 vs.vehicle group, **=p<0.01 vs. vehicle group, ***=p<0.001 vs. vehiclegroup, ^=p<0.05 vs. 1 mg/kg SB269970 group, and #=p<0.001 vs. 1 mg/kgSB269970 group. In FIG. 1B, *p<0.05 vs. vehicle group, **=p<0.01 vs.vehicle group, and ^=p<0.01 vs. 0.1 mg/kg Compound A group.

FIGS. 2A and 2B depict effects of administration of the indicated dosesof the SSRI,1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile(citalopram) alone and when co-administered independently with theindicated doses of each of the 5-HT receptor antagonists, SB269970 andCompound A, on mice in the setting of the tail suspension test (FIGS. 2Aand 2B, respectively). Data bars represent the mean±SEM and n=8.**=p<0.01 vs. vehicle group, ***=p<0.001 vs. vehicle group, ^=p<0.05 vs.citalopram alone, and #=p<0.001 vs. citalopram alone.

FIGS. 3A and 3B depict effects of administration of the indicated dosesof citalopram alone and when co-administered with the indicated doses ofeach of the 5-HT receptor antagonists, SB269970 and Compound A, in thesetting of the locomotor activity test. Data bars represent themean±SEM, with n=12 and p>0.05.

FIGS. 4A and 4B depict effects of administration of sub-efficaciousdoses of either SB269970 alone, Compound A alone, or citalopram alone,and of co-administration of citalopram independently with SB269970 (FIG.4A) and Compound A (FIG. 4B). Data bars represent the mean±SEM; n=8 and***=p<0.001 vs. vehicle group.

FIGS. 5A-5D depict effects on prefrontal cortical dialysate 5-HT levelsfrom rats that were administered the indicated doses of eithercitalopram, SB269970, or Compound A, or co-administered the indicateddoses of citalopram and SB269970 or citalopram and Compound A. All ratswere administered agents after measuring stable baseline levels over90-minute fractions, as indicated with arrow. In FIGS. 5A and 5C, databars represent the mean±SEM; n=3-4. In FIGS. 5B and 5D, area under thecurve (AUC) values of data in FIGS. 5A and 5B, respectively, arepresented. ***=p<0.001 vs. vehicle; #=p<0.01 vs. citalopram alone.

FIGS. 6A-6D depict effects on prefrontal cortical dialysate 5-HT levelsfrom rats that were administered the indicated doses of eithercitalopram, SB269970, or Compound A, or co-administered the indicateddoses of citalopram and SB269970 or citalopram and Compound A. In FIGS.6A and 6C, data bars represent the mean±SEM; n=3-4. In FIGS. 6B and 6D,area under the curve (AUC) values of data in FIGS. 6A and 6B,respectively, are presented. ***=p<0.01 vs. vehicle.

FIGS. 7A and 7B depict plasma (FIG. 7A) and brain (FIG. 7B) citalopramlevels in rats after subcutaneous administration of citalopram alone (3mg/kg) or subcutaneous co-administration of citalopram (3 mg/kg) andSB269970 (10 mg/kg). Data represents mean±SEM; n=3.

FIGS. 8A and 8B illustrates the duration of time spent awake followingthe co-administration of citalopram (1 mg/kg) and Compound A (0.3 mg/kg)(A) or SB269970 (B) (10 mg/kg) (n=9, average±S.E.M.).

FIGS. 9A and 9B depict duration of NREM sleep following theco-administration of citalopram (1 mg/kg) and Compound A (0.3 mg/kg) (A)or SB269970 (B) (10 mg/kg) (n=9, average±S.E.M.).

FIGS. 10A and 10B illustrate absolute NREM delta power following theco-administration of citalopram (1 mg/kg) and Compound A (0.3 mg/kg) (A)or SB269970 (B) (10 mg/kg) (n=9, average±S.E.M.).

FIGS. 11A and 11B show REM sleep following the co-administration ofcitalopram (1 mg/kg) and Compound A (0.3 mg/kg) (A) or SB269970 (B) (10mg/kg) (n=9, average±S.E.M.).

FIGS. 12A and 12B illustrate the number of micro-arousals following theco-administration of citalopram (1 mg/kg) and Compound A (0.3 mg/kg) (A)or SB269970 (B) (10 mg/kg) (n=9, average±S.E.M.).

DETAILED DESCRIPTION OF INVENTION AND ITS PREFERRED EMBODIMENTS

For the sake of brevity, the disclosures of all patents and otherpublications cited in this specification are incorporated by referenceherein.

In one embodiment, the invention relates to a method of treating asubject suffering from or diagnosed with a serotonin-mediated disease orcondition, comprising administering to a subject in need of suchtreatment: an amount of a 5-HT7 receptor antagonist and an amount of anSRI and a 5-HT7 receptor antagonist, the amounts together providing aneffective combined amount. In another embodiment, the invention relatesto a pharmaceutical composition for treating a serotonin-mediateddisease or condition, comprising: (a) (i) an amount of a 5-HT7 receptorantagonist, and (ii) an amount of a selective serotonin reuptakeinhibitor, such amounts together providing an effective combined amount;and (b) a pharmaceutically acceptable excipient.

The terms “including”, “containing”, and “comprising” are used herein intheir open, non-limiting sense.

The term “subject” refers to a mammalian patient in need of therapeuticor prophylactic treatment. Preferably, subjects treated in accordancewith the invention are human.

The term “treat” or “treating” is intended to refer to administration ofa composition to a subject for the therapeutic or prophylactic benefitof reversing, ameliorating, alleviating, inhibiting the progress of,lessening the severity of, or preventing a disease, medical condition,or disorder. Symptoms and disease states are intended to be includedwithin the scope of diseases, conditions, and disorders.

In accordance with the invention, effective amounts of an SRI and a5-HT7 receptor antagonist are administered to a subject to treatserotonin-mediated diseases and conditions (or their associatedsymptoms) that are mediated through increasing the release of serotonin,inhibiting its reuptake, or both, or by increasing activity ofserotonergic neurons, such as those associated with aberrant 5-HT7receptor levels or serotonin reuptake activity or function. Exemplarymedical conditions, diseases, and disorders include cognitive andpsychiatric disorders, sleep disorders, vascular disorders,gastrointestinal disorders, urinary incontinence, aberrant hormonesecretion, metabolic disorders, septic shock, renal disorders,inflammation and inflammatory disorders (see, e.g., Hedlund et al.,Trends Pharmacol. Sci. (2004), 25(9):481-486; Thomas et al., Curr. DrugTargets CNS Neurol. Disord., (2004), 3(1):81-90; Pouzaet B, CNS DrugRev., (2002), 8(1):90-100; Eglen et al., TiPS (1997), 18:104-107;Vanhoenacker et al., TiPS (2000), 21:70-77; Glennon R A, J. Med. Chem.(2003), 46(14):2795-2812; Ni et al., Clin. Exp. Pharmacol. Physiol(2006), 33(7):575-583; Martel F, Pharmacol. Res. (2006), 54:73-76; andMurphy et al., Genes, Brain & Behav. (2003), 2(6):350-364.

Cognitive and psychiatric disorders include depression/anxiety,generalized anxiety disorder, schizophrenia, bipolar disorders,psychotic disorders, obsessive-compulsive disorder, mood disorders,post-traumatic stress and other stress-related disorders, learning andmemory dysfunction, migraine, disorders associated with nociception andpain, arousal and vigilance disorders, disorders associated withaberrant sensory perception, disorders associated with aberrant motoractivity, disorders associated aberrant thermoregulation, sexualdysfunction, centrally mediated hypotension, alcohol abuse, drug abuse,and other addictive disorders, metabolic disorders, hormonal imbalances,eating disorders, and obesity.

Sleep disorders include insomnia, disturbed sleep, narcolepsy (with orwithout associated cataplexy), cataplexy, sleep/wake disturbances,idiopathic somnolence, excessive daytime sleepiness (EDS), circadianrhythm disorders, fatigue, lethargy, and jet lag. Fatigue and/or sleepimpairment may be caused by or associated with various sources, such as,for example, sleep apnea, perimenopausal hormonal shifts, Parkinson'sdisease, multiple sclerosis (MS), depression, chemotherapy, or shiftwork schedules.

Vascular disorders include cardiovascular disorders, cardiovascularshock and arrhythmias, hypotension, ischemias, and stroke.

Gastrointestinal disorders include gastric motility disorders, diarrhea,spastic colon and irritable bowel disorders.

In addition, combination therapies of the present invention may be usedin the treatment or prevention of various ocular disorders includingglaucoma, optic neuritis, diabetic retinopathy, retinal edema, andage-related macular degeneration.

In certain preferred embodiments, the serotonin-mediated disease ordisorder is selected from depression, anxiety, sleep or wakedisturbances, jet-lag, migraine, urinary incontinence, gastric motility,and irritable bowel disorders.

The term “effective combined amount” means an effective or complementaryamount or dose of a 5-HT7 receptor antagonist and an effective orcomplementary amount of an SRI that together are sufficient to generallybring about or effect a desired therapeutic or prophylactic benefit topatients in need of treatment of a serotonin-mediated disease orcondition. The benefit of the effective combined amount of the twoagents may be advantageously supra-additive or synergistic, relative tothe benefit that would be achieved by administration of the same totalamount (i.e., the numerical amount equivalent to the combined effectiveamount) of one of the agents administered alone, or it may beameliorative (i.e., the amount of one agent may lessen or reverse anundesirable effect typically induced by administration of the otheragent alone).

The term “effective amount” means an amount or dose of a 5-HT7 receptorantagonist agent or an SRI agent (as the case may be) that is sufficientto generally bring about or effect a therapeutic or prophylactic benefitwhen administered alone to patients in need of treatment of aserotonin-mediated disease or condition.

The term “complementary amount” means an amount or dose of a 5-HT7receptor antagonist agent or an SRI agent (as the case may be) that is:(i) a potentiating amount, which is a dose insufficient to generallybring about or effect the therapeutic or prophylactic benefit whenadministered alone to patients in need of treatment of aserotonin-mediated disease or condition (i.e., it is sub-efficacious)but which potentiates or augments the effect of the other 5-HT-mediatingagent (the SRI or 5-HT7 receptor antagonist, as the case may be) withwhich it is administered; and/or (ii) an ameliorative amount, which is adose of one agent that is sufficient to reverse or lessen the severityof an undesirable side effect generally caused by administration of theother agent alone.

In certain embodiments, an effective amount of a 5-HT7 receptorantagonist may be combined with an effective amount of an SRI to providea therapeutic composition comprising an effective combined amount of thetwo agents. In preferred embodiments, an effective amount of a 5-HT7receptor antagonist agent is combined with a complementary amount of anSRI agent to provide a therapeutic composition comprising an effectivecombined amount of the two agents. In other preferred embodiments, aneffective amount of an SRI is combined with a complementary amount of a5-HT7 receptor antagonist to provide a therapeutic compositioncomprising an effective combined amount of the two agents. In anespecially preferred embodiment, an effective amount of an SSRI such ascitalopram is combined with a complementary amount of a 5-HT7 receptorantagonist sufficient to ameliorate an increase in sleep fragmentationinduced by the SSRI, more preferably, to also potentiate the effect ofthe SSRI.

Suitable amounts of the 5-HT7 receptor antagonists and SRIs,individually and together, may be ascertained by routine methods, suchas modeling, dose escalation studies, or other clinical trials, and bytaking into consideration routine factors, e.g., the mode or route ofadministration or drug delivery, the pharmacokinetics of the agent, theseverity and course of the disease, disorder, or condition, thesubject's previous or ongoing therapy, the subjects weight, healthstatus, and response to drugs, and the judgment of the treatingphysician. An exemplary oral dose is in the range of from about 0.001 toabout 200 mg of each 5-HT7 receptor antagonist agent and SRI per kg ofsubject's body weight per 24 hours, or preferably about 0.05 to 100mg/kg/day, or about 1 to 50 mg/kg/day, in single or divided dosage units(e.g., BID, TID, QID). For a 70-kg human, an illustrative range for adosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about2.5 g/day, or about 0.01 to about 1 g/day, or about 0.001 to about 0.5g/day, of each active agent, either in separate dosage forms or in acombined dosage form. Infusion doses can range from about 1 to 1000μg/kg/min of each agent, admixed with a pharmaceutical carrier over aperiod ranging from several minutes to several days. For an exemplarytopical administration, the active agents may be admixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle. Other suitable dosages for the active ingredients oragents may be routinely determined, e.g., in light of the dosages for5-HT7 receptor antagonists and SRIs exemplified in the art and ininvestigative and commercial products. For additional guidance, see,e.g., Simons et al., New England J Medicine (1994), 330:1663-1670.

Once improvement of the disease or condition has occurred, the dose maybe adjusted for preventative or maintenance treatment, if indicated. Forexample, the dosage or the frequency of administration, or both, may bereduced as a function of the reduction of intensity or frequency ofsymptoms, to a level at which the desired therapeutic or prophylacticeffect is maintained. Of course, if the medical condition has beenalleviated to an appropriate level, treatment may cease. Patients may,however, be intermittently treated on a long-term basis with thecombination therapy of the invention upon any recurrence of the medicalcondition or symptoms thereof.

The combination therapies of the present invention may be used to treatvarious serotonin-mediated diseases and conditions, such as thoseassociated with 5-HT activity in either peripheral systems or centralnervous systems. For diseases and conditions in which the CNS isinvolved, the selected 5-HT7 receptor antagonist and/or SRI preferablypossess centrally acting characteristics. Centrally acting 5-HT7receptor antagonists and SRIs are those that readily enter the centralnervous system (CNS) across the blood-brain barrier (BBB) or have highBBB permeability. See, e.g., Frazer A, J. Clin. Psychiatry (2001), 62Suppl. 12:16-23, Ohtsuki S, Biol. Pharm. Bull. (2004), 27(10):1489-1496; Ishiguro et al., Drug Metabolism & Disposition (2004), 32(5):519-524; Hansen et al., Drugs Aging (2005), 22(4): 289-96; Welch et al.,Clin. Allergy Immunol. (2002), 17: 337-88.

Compounds having 5-HT7 receptor antagonizing activity or SRI activitythat are known or that become available may be tested for centralactivity (i.e., to determine if they are centrally acting) by measuringtheir ability to cause, for example, anti-depressive effects in humans.A 5-HT7 receptor antagonist or SRI that is positive in such a screen,i.e., that causes significant anti-depressive effects in humans, is onethat may be selected for use in the invention. Alternatively, to screencompounds for 5-HT7 receptor antagonizing activity or SRI activityuseful in the invention artisans may directly measure the binding ofsuch compounds to human brain 5-HT7 receptors or SERT in vivo usingpositron emission tomography (PET) (see, e.g., Yanai et al., Br. J.Pharmacol. (1995), 116:1649-1655; Yania et al., J. Neurochem. (1992),59:128-136; Tagawa et al., Br. J. Clin. Pharmacol. (2001), 52(5): 501;and Tashiro et al., British J. Clin. Pharmacology (2005), 61(1): 16-26).In another technique, this property may be measured in animals, e.g., byquantitating the amount of the candidate 5-HT7 receptor antagonist orSRI compound in the brain by LC/MS after oral dosing (Chen et al., DrugMetabolism and Disposition (2003), 31:312-318). In another assayemploying animals, the ratio of therapeutic dose to lethal dose inguinea pigs may be used as a measure of central activity, where brainpenetration decreases as ratios increase (Van Wauwe et al., Arch. Int.Pharmacodyn. Ther. (1982), 251:39-51). Alternatively, 5-HT7 receptorantagonist and SRI candidate compounds may be assayed for activity bytesting their ability to inhibit the in vitro binding of known highaffinity 5-HT7 receptor-binding or SERT-binding compounds, respectively.

Another in vitro method for screening for centrally acting compounds isthe immobilized artificial membrane phosphatidylcholine columnchromatography test described by Yoon et al., J. Biomolecular Screening(2006), 11(1):13-20. Alternatively, a battery of tests may be employed,such as the subjective sleepiness test (evaluated by Stanford SleepinessScale), objective psychomotor test, and measurement of histamineH₁-receptor occupancy in the brain as described by Tashiro et al., J.Clinical Pharmacology (2004), 44:890-900.

Suitable 5-HT7 receptor antagonists may also be selected from thevarious compounds known in the art having 5-HT7 receptor antagonisticactivity. Exemplary 5-HT7 receptor-binding compounds include 5-HT,carboxamidotryptamine (5-CT), metergoline, methiothepin, methysergide,2-Br lysergic acid diethylamide (2-Br LSD), 1-naphthylpiperazine, andclozapine (see, e.g., Glennon et al., J. Med. Chem. (2003),46(14):2795-2812) and radiolabeled forms of these compounds. ExemplarySRIs include SERT-binding compounds or SSRIs such as fluoxetine,citalopram, fluvoxamine, paroxetine and sertraline, quinidine,verapamil, propranolol, amiloride, nicotine, clonidine, cocaine,amphetamine, and (+)-3,4-methylene-dioxymethamphetamine (MDMA) (see,e.g., Martel, Pharmacol. Research (2006), 54:73-76; and Keating et al.,Life Sci (2004), 76:109-119).

In preferred embodiments, the 5-HT7 receptor antagonist of thecombination therapy of the invention is selected from the 5-HT7antagonist compounds specifically described or from the species coveredby the general structural formulae in: U.S. Pat. No. 6,025,367; USPatent Application Publication No. 2005/0119295; U.S. patent applicationSer. No. 11/460,294, filed Jul. 27, 2006 ; International PublicationNos. WO 2005/040169, WO 2005/005387, WO 2002/062788, WO 2001/57039, WO2001/029029, WO 2000/73299, WO 2000/056712, WO 2000/037082, WO 99/54303,WO 99/24022, WO 99/22804, WO 98/00400, WO 98/31354, WO 97/49695, WO97/48681, WO 97/29097, and WO 96/32944; and EP 937715; the disclosuresof which are incorporated by reference herein.

Additionally, preferred 5-HT7 receptor antagonists are those describedin US Patent Application Publication No. 2005/0119295 and U.S.Provisional Patent Application No. 60/746,497, filed May 5, 2006possessing activity (K_(i)) against the 5-HT7 receptor≦1000 nM.Particularly preferred 5-HT7 receptor antagonists are selected from thecompounds listed below and their pharmaceutically acceptable salts(where a free acid or base is listed) or free acid/base form (where asalt is listed):

-   1-Benzyl-3-(4-nitro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   1-Benzyl-3-(5-chloro-thiophen-2-yl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   1-Benzyl-3-thiophen-2-yl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   1-(3-Chloro-benzyl)-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   1-Benzyl-3-(3-fluoro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   3-(4-Chloro-phenyl)-1-(2-fluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   1-(3-Chloro-benzyl)-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   1-(2-Chloro-benzyl)-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   1-(4-Chloro-benzyl)-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   1-Benzyl-3-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   1-(4-Methoxy-benzyl)-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   1-Benzyl-2-methyl-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   1-Benzyl-3-p-tolyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   3-Benzo[1,3]dioxol-5-yl-1-benzyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   1-Benzyl-3-(4-fluoro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   1-Butyl-3-p-tolyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   1-Benzyl-3-(4-bromo-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   1-Benzyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   1-Benzyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   1-Benzyl-3-phenyl-1,4,5,6,7,8-hexahydro-pyrrolo[2,3-d]azepine;-   1-Benzyl-3-(5-methyl-thiophen-2-yl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   1-Benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-pyrrolo[2,3-d]azepine;-   1-Benzyl-3-(5-chloro-thiophen-2-yl)-1,4,5,6,7,8-hexahydro-pyrrolo[2,3-d]azepine;-   1-(4-Chloro-benzyl)-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   1-Benzyl-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   1-Benzyl-3-(3-chloro-phenyl)-1,4,5,6,7,8-hexahydro-pyrrolo[2,3-d]azepine;-   1-Benzyl-3-(4-methoxy-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   1-Benzyl-3-(4-chloro-phenyl)-5-ethyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   1-Benzyl-3-(4-chloro-phenyl)-5-isopropyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   1-Benzyl-3-(4-chloro-phenyl)-5-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   1-Benzyl-3-(3-chloro-4-fluoro-phenyl)-5-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   1-Benzyl-5-isopropyl-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;-   1-Benzyl-3-(4-trifluoromethyl-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   1-Benzyl-3-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   1-Benzyl-3-(2-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   1-Benzyl-3-(3-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   1-Benzyl-3-(4-fluoro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   1-Benzyl-3-(3,4-dichloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   1-[4-(1-Benzyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-phenyl]-ethanone;-   1-Benzyl-3-(4-trifluoromethoxy-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   1-Benzyl-3-(3-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   4-(1-Benzyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile;-   1-(4-Chloro-benzyl)-3-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   1-(4-Chloro-benzyl)-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   1-Benzyl-3-phenyl-6-propyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   1-Benzyl-6-isopropyl-3-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   1-Benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   1-Benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,5-triaza-azulene;-   3-(4-Chloro-phenyl)-1-methyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-2-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-ethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-2-ethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-propyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-2-propyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   1-Butyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Butyl-3-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(2-cyclohexyl-ethyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-2-(2-cyclohexyl-ethyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-phenethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-2-phenethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(4-fluoro-3-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(3-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(4-fluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(3-fluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(4-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(3,4-difluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(3-nitro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(3-fluoro-4-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(3,4-dimethyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   5-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-pentanoic    acid methyl ester;-   5-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-pentan-1-ol;-   5-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-pentanoic    acid methyl ester;-   5-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-pentan-1-ol;-   4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-butyric    acid methyl ester;-   4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-butan-1-ol;-   3-(4-Chloro-phenyl)-2-(3,4-difluoro-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-2-(4-methyl-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(3-fluoro-4-methoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-2-(3-fluoro-4-methoxy-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(4-nitro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   4-(3-Phenyl-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl)-phenylamine;-   N-[4-(3-Phenyl-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl)-phenyl]-methanesulfonamide;-   N,N-[4-(3-phenyl-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl)-phenyl]-dimethanesulfonamide;-   1-Benzyl-3-p-tolyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-thiophen-2-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   1-Benzyl-3-thiophen-2-yl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(3-methoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(2-fluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(2-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(2,4-difluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(2-methoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   1-(2-Chloro-benzyl)-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   1-But-3-enyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   1-(2-Bromo-benzyl)-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   1-(4-Bromo-benzyl)-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(2-ethyl-butyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(5-chloro-thiophen-2-ylmethyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   1-(3-Bromo-benzyl)-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-cyclohexylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-isobutyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   1-Benzo[1,3]dioxol-5-ylmethyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(tetrahydro-pyran-4-ylmethyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(2,6-difluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-2-cyclohexylmethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(4-methoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(3-methyl-butyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(2-trifluoromethyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-2-(2-methyl-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Benzyl-3-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(4-methoxy-2-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-2-(2,4-difluoro-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   5-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-ylmethyl]-furan-2-carboxylic    acid ethyl ester;-   3-(4-Chloro-phenyl)-2-isobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-2-(2-methoxy-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Benzyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-prop-2-ynyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-pentafluorophenylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-2-thiophen-2-ylmethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(2,4,6-trifluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-benzonitrile;-   3-(4-Chloro-phenyl)-2-(5-chloro-thiophen-2-ylmethyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-2-(2,6-difluoro-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-2-(2-trifluoromethyl-benzyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-naphthalen-2-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-2-(2-ethyl-butyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-naphthalen-1-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Benzo[1,3]dioxol-5-ylmethyl-3-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   [3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-acetic    acid methyl ester;-   2-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-N-methyl-acetamide;-   3-(4-Chloro-phenyl)-2-pentafluorophenylmethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-phenol;-   4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-phenol;-   4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-3-methyl-phenol;-   4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-benzene-1,2-diol;-   4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-2-fluoro-phenol;-   4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-ylmethyl]-2-fluoro    phenol;-   2-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-phenol;-   4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-ylmethyl]-3-methyl-phenol;-   2-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-ylmethyl]-phenol;-   1-Benzyl-3-(4-chloro-phenyl)-6-methyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   1-Benzyl-3-(4-chloro-phenyl)-6-ethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-6-(3,4-dimethoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   1-Butyl-3-(4-chloro-phenyl)-6-(3,4-dimethoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   1-Benzyl-3-(4-chloro-phenyl)-6-(3,4-dimethoxy-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   [1-Benzyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulen-6-yl]-acetic    acid methyl ester;-   2-[1-Benzyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulen-6-yl]-ethanol;-   3-(4-Chloro-phenyl)-1-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(2-methyl-benzyl)-4,5,6,7,8,9-hexahydro-1H-1,2,6-triaza-cyclopentacyclooctene;-   3-(4-Chloro-phenyl)-1-(2-methyl-benzyl)-4,5,6,7,8,9-hexahydro-1H-1,2,7-triaza-cyclopentacyclooctene;-   3-(4-Chloro-phenyl)-1-(2-methyl-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine;-   2,3-Diphenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Cyclohexyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-2-cyclohexyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Cyclohexyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Cyclopentyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-2-cyclopentyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Cyclopentyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-(1-Ethyl-propyl)-3-(3-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-(1-Ethyl-propyl)-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-(1-Ethyl-propyl)-3-thiophen-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-(1-Ethyl-propyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-2-(2,2,2-trifluoro-ethyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-(2,2,2-Trifluoro-ethyl)-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Isopropyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-(1-Ethyl-propyl)-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Cyclopentyl-3-thiophen-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Ethyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Ethyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Ethyl-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-(3-Chloro-phenyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-(3-Fluoro-phenyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-(2-Chloro-phenyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Phenyl-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Fluoro-phenyl)-2-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-2-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(3-Chloro-phenyl)-2-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Phenyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2,3-Diphenyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine;-   3-Phenyl-2-(3-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Methoxy-phenyl)-2-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   6-Methyl-2,3-diphenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Isopropyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Ethyl-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   4-(2-Isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile;-   2-Isopropyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Ethyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-tert-Butyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-tert-Butyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Cyclopentyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Cyclopentyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(3-Chloro-phenyl)-2-cyclopentyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Cyclopentyl-3-(4-methoxy-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-(3,3-Dimethyl-cyclopentyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-(3,3-Dimethyl-cyclopentyl)-3-(4-fluoro-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Cyclohexyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Cyclohexyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Cyclohexyl-3-(4-methoxy-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   4-(2-Cyclohexyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile;-   3-(3-Chloro-phenyl)-2-cyclohexyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   {4-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-phenyl}-methyl-amine;-   3-(4-Fluoro-phenyl)-2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine;-   2-Cyclopentyl-3-furan-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Cyclopentyl-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-tert-Butyl-3-thiophen-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-tert-Butyl-3-furan-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Cyclopentyl-3-(3,4-difluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-cyclobutyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-2-cyclobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-cyclohexyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-tert-Butyl-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(3-Chloro-4-fluoro-phenyl)-2-cyclopentyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Isopropyl-3-(4-methoxy-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Isopropyl-3-(4-isopropyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Isopropyl-3-m-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Isopropyl-3-o-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Isopropyl-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(2-Chloro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Isopropyl-3-(4-nitro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-cycloheptyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-cyclooctyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Ethyl-3-(4-ethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   4-(2-Ethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile;-   3-(4-Fluoro-phenyl)-2-isopropyl-6-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Fluoro-phenyl)-2,6-diisopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Ethyl-3-(4-isopropyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Ethyl-3-(4-methoxy-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Ethyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Ethyl-3-o-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(2-Chloro-phenyl)-2-ethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Ethyl-3-(2-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(2,4-Dichloro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   6-Benzyl-3-(4-fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Fluoro-phenyl)-2-isopropyl-6-(3-phenyl-propyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Fluoro-phenyl)-2-isopropyl-6-phenethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   1-Benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene    citrate salt;-   2-Cyclobutyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Cyclobutyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Cyclobutyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Cyclobutyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Cyclopropyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Cyclopropyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Cyclopropyl-3-thiophen-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   4-(2-Cyclopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile;-   6-Benzyl-2-isopropyl-3-phenyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine;-   2-Isopropyl-3-phenyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine;-   6-Benzyl-2-isopropyl-3-thiophen-3-yl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine;-   6-Benzyl-2-isopropyl-3-p-tolyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine.-   6-Benzyl-3-(4-fluoro-phenyl)-2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine;-   3-(4-Fluoro-phenyl)-2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine;-   2-Isopropyl-3-p-tolyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine;-   2-sec-Butyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-sec-Butyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-sec-Butyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-sec-Butyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Cyclopentyl-3-(4-fluoro-phenyl)-6-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   6-Benzyl-3-(4-fluoro-phenyl)-2-isopropyl-8-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Fluoro-phenyl)-2-isopropyl-8-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Fluoro-phenyl)-2-isopropyl-4-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Cyclopentyl-3-(4-fluoro-phenyl)-5-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Cyclopentyl-7-methyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Isopropyl-7-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Isopropyl-5-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Fluoro-phenyl)-2-isopropyl-7-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Fluoro-phenyl)-2-isopropyl-5-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   2-Isopropyl-7-methyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-pyridin-4-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-pyridin-2-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-pyridin-3-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(tetrahydro-pyran-4-yl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(4-methyl-cyclohexyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   {2-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-ethyl}-dimethyl-amine.-   2-[1-Benzyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulen-6-yl]-acetamide;-   3-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-propionitrile;-   3-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-propionitrile;-   3-(4-Chloro-phenyl)-2-cycloheptyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene;-   1-(4-Chloro-benzyl)-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,5-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(3,4-difluoro-benzyl)-1,4,5,6,7,8-hexahydro-1,2,5-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(3-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,5-triaza-azulene;-   3-(4-Chloro-phenyl)-1-(4-fluoro-3-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,5-triaza-azulene;-   3-(4-Fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene    citrate salt; and-   2-Cyclopentyl-3-(4-fluoro-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene    citrate salt.

In other preferred embodiments, the 5-HT7 receptor antagonist isselected from compounds of the following Formulae (I) or (II):

wherein

-   m is 1, 2, or 3;-   n is 1, 2, or 3;-   where when m and n are both present, m+n is greater than or equal to    2, and is less than or equal to 4;-   R^(a) and R^(b) are each independently —H, —C₁₋₇alkyl, or    —C₃₋₇cycloalkyl, or R^(a) and R^(b) taken together with the nitrogen    of attachment form piperidinyl, pyrrolidinyl, morpholinyl,    thiomorpholinyl, or piperazinyl, where each R^(a) and R^(b) is    optionally and independently substituted with —C₁₋₄alkyl;-   q is 0 or 1;-   A is >NR¹, >CHNR^(c)R^(d), >CHOH, or —CH₂—, wherein    -   R¹ is selected from the group consisting of —H, —C₁₋₇alkyl,        —C₃₋₇cycloalkyl, and benzyl, where each alkyl, cycloalkyl, or        benzyl is optionally mono-, di-, or tri-substituted with R^(e);        -   R^(e) is selected from the group consisting of —C₁₋₄alkyl,            —C₂₋₄alkenyl, —C₂₋₄alkynyl, —C₃₋₆cycloalkyl, halo, —CF₃,            —OH, —OC₁₋₄alkyl, —OCF₃, —N(R^(f))R^(g) (wherein R^(f) and            R^(g) are independently —H or —C₁₋₄alkyl, or R^(f) and R^(g)            taken together with the nitrogen of attachment form            piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, or            piperazinyl), —C(O)N(R^(f))R^(g), —N(R^(h))C(O)R^(h),            —N(R^(h))SO₂C₁₋₇alkyl (wherein R^(h) is —H or —C₁₋₄alkyl, or            two R^(h) in the same substituent taken together with the            amide of attachment form an otherwise aliphatic 4- to            6-membered ring), —S(O)₀₋₂—C₁₋₄alkyl, —SO₂N(R^(f))R^(g),            —SCF₃, —C(O)C₁₋₄alkyl, —CN, —COOH, and —COOC₁₋₄alkyl;    -   R^(c) and R^(d) are independently selected from the group        consisting of —H, —C₁₋₇alkyl, —C₃₋₇alkenyl, —C₃₋₇alkynyl,        —C₃₋₇cycloalkyl, —C₁₋₇alkyl C₃₋₇cycloalkyl, and —C₃₋₇cycloalkyl        C₁₋₇alkyl, or R^(c) and R^(d) taken together with the nitrogen        of attachment form piperidinyl, pyrrolidinyl, morpholinyl,        thiomorpholinyl, or piperazinyl, where each R^(c) and R^(d) is        optionally and independently substituted with R^(e);-   R³ is —C₁₋₄alkyl, —C₁₋₄alkenyl, or benzyl, each optionally    substituted with —C₁₋₃alkyl, —OH, or halo, or two R³ substituents    taken together form C₂₋₅alkylene optionally substituted with    —C₁₋₃alkyl, —OH, or halo;-   r is 0 or is an integer less than or equal to m+n+1;-   Ar is an aryl or heteroaryl ring selected from the group consisting    of:    -   a) phenyl, optionally mono-, di-, or tri-substituted with R^(i)        or di-substituted on adjacent carbons with —OC₁₋₄alkyleneO-,        —(CH₂)₂₋₃NH—, —(CH₂)₁₋₂NH(CH₂)—, —(CH₂)₂₋₃N(C₁₋₄alkyl)-, or        —(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—;        -   R^(i) is selected from the group consisting of —C₁₋₇alkyl,            —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, halo, —CF₃,            —OH, —OC₁₋₇alkyl, —OCF₃, —OC₃₋₇alkenyl, —OC₃₋₇alkynyl,            —N(R^(j))R^(k) (wherein R^(j) and R^(k) are independently —H            or —C₁₋₄alkyl), —C(O)N(R^(j))R^(k), —N(R^(j))C(O)R^(k),            —N(R^(j))SO₂C₁₋₆alkyl, —S(O)₀₋₂—C₁₋₆alkyl,            —SO₂N(R^(j))R^(k), —SCF₃, —C(O)C₁₋₆alkyl, —NO₂, —CN, —COOH,            and —COOC₁₋₇alkyl;    -   b) a monocyclic aromatic hydrocarbon group having five ring        atoms, having a carbon atom which is the point of attachment,        having one carbon atom replaced by >O, >S, >NH, or        >N(C₁₋₄alkyl), having up to two additional carbon atoms        optionally replaced by —N═, optionally mono- or di-substituted        with R^(i);    -   c) a monocyclic aromatic hydrocarbon group having six ring        atoms, having a carbon atom which is the point of attachment,        having one or two carbon atoms replaced by —N═, optionally mono-        or di-substituted with R^(i); and    -   d) phenyl or pyridyl, substituted with a substituent selected        from the group consisting of phenyl, phenoxy, pyridyl,        thiophenyl, oxazolyl, and tetrazolyl, where the resultant        substituted moiety is optionally further mono-, di-, or        tri-substituted with R^(i);-   ALK is a branched or unbranched C₁₋₇alkylene, C₂₋₇alkenylene,    C₂₋₇alkynylene, C₃₋₇cycloalkylene, or C₃₋₇cycloalkenylene,    optionally mono-, di-, or tri-substituted with R^(m);    -   R^(m) is selected from the group consisting of halo, —CF₃, —OH,        —OC₁₋₇alkyl, —OC₃₋₇cycloalkyl, —OCF₃, —N(R^(p))R^(s) (wherein        R^(p) and R^(s) are independently —H or —C₁₋₇alkyl),        —C(O)N(R^(p))R^(s), —N(R^(t))C(O)R^(t), —N(R^(t))SO₂C₁₋₆alkyl        (wherein R^(t) is —H or —C₁₋₇alkyl), —S(O)₀₋₂—C₁₋₆alkyl,        —SO₂N(R^(p))R^(s), —SCF₃, —CN, —NO₂, —C(O)C₁₋₇alkyl, —COOH, and        —COOC₁₋₇alkyl;-   CYC is —H or is a ring system selected from the group consisting of:    -   i) phenyl, optionally mono-, di-, or tri-substituted with R^(u)        or di-substituted on adjacent carbons with —OC₁₋₄alkyleneO-,        —(CH₂)₂₋₃NH—, —(CH₂)₁₋₂NH(CH₂)—, —(CH₂)₂₋₃N(C₁₋₄alkyl)-, or        —(CH₂)₁₋₂N(C₁₋₄alkyl)(CH₂)—;        -   R^(u) is selected from the group consisting of —C₁₋₇alkyl,            —C₃₋₇cycloalkyl, phenyl, benzyl, halo, —CF₃, —OH,            —OC₁₋₇alkyl, —OC₃₋₇cycloalkyl, -Ophenyl, -Obenzyl, —OCF₃,            —N(R^(v))R^(w) (wherein R^(v) and R^(w) are independently —H            or —C₁₋₇alkyl, or R^(v) and R^(w) taken together with the            nitrogen of attachment form piperidinyl, pyrrolidinyl,            morpholinyl, thiomorpholinyl, or piperazinyl, where each            R^(v) and R^(w) is optionally and independently substituted            with —OH or —C₁₋₇alkyl), —C(O)N(R^(v))R^(w),            —N(R^(x))C(O)R^(x), —N(R^(x))SO₂C₁₋₆alkyl (wherein R^(x) is            —H or —C₁₋₇alkyl, or two R^(x) in the same substituent taken            together with the amide of attachment form an otherwise            aliphatic 4- to 6-membered ring), —N—(SO₂C₁₋₆alkyl)₂,            —S(O)₀₋₂—C₁₋₆alkyl, —SO₂N(R^(v))R^(w), —SCF₃,            —C(O)C₁₋₆alkyl, —NO₂, —CN, —COOH, and —COOC₁₋₇alkyl;    -   ii) a monocyclic aromatic hydrocarbon group having five ring        atoms, having a carbon atom which is the point of attachment,        having one carbon atom replaced by >O, >S, >NH, or        >N(C₁₋₄alkyl), having up to one additional carbon atoms        optionally replaced by —N═, optionally mono- or di-substituted        with R^(u);    -   iii) a monocyclic aromatic hydrocarbon group having six ring        atoms, having a carbon atom which is the point of attachment,        having one or two carbon atoms replaced by —N═, optionally mono-        or di-substituted with R^(u); and    -   iv) a non-aromatic heterocyclic ring having 4 to 8 members, said        ring having 0, 1, or 2 non-adjacent heteroatom members selected        from the group consisting of O, S, —N═, >NH, and >N(C₁₋₄alkyl),        having 0, 1, or 2 double bonds, having 0, 1, or 2 carbon members        which is a carbonyl, optionally having one carbon member which        forms a bridge, having 0 to 5 substituents R^(u), and where when        q is 0, said ring has a carbon atom which is the point of        attachment;-   and where when the compound is of Formula (I):    -   (a) when ALK is methylene, ethylene, propylene, or isopropylene,        CYC is —H, Ar is phenyl or mono-substituted phenyl, m is 2, n is        1, and A is >NR¹, then R¹ is not —C₁₋₄alkyl or benzyl;    -   (b) when q is 0, CYC is phenyl, Ar is phenyl or 3-chlorophenyl,        m is 2, and n is 1, then A is not unsubstituted —CH₂—; and    -   (c) when q is 0, CYC is 2-pyridyl, Ar is 2-pyridyl, m is 2, and        n is 1, then A is not unsubstituted —CH₂—;-   and enantiomers, diastereomers, hydrates, solvates, and    pharmaceutically acceptable salts, esters and amides of such    compounds.

Further preferred 5-HT7 receptor antagonists include those described inU.S. patent application Ser. No. 11/460,294, filed Jul. 27, 2006 havingan activity (K_(i)) against the 5-HT7 receptor≦1000 nM. Especiallypreferred 5-HT7 receptor antagonists are the compounds listed below andtheir pharmaceutically acceptable salts (where a free acid or base islisted) or free acid/base form (where a salt is listed):

-   2-tert-Butyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;-   2-Cyclopentyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;-   2-Isobutyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine;-   2-Cyclopentyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;-   2-Cyclopentyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;-   2-Cyclopentyl-4-(4-methoxy-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;-   4-(2-Cyclopentyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)-benzonitrile;-   4-(4-Fluoro-phenyl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine    hydrochloride;-   2-Benzyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;-   2-Benzyl-4-(4-trifluoromethyl-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;-   2-(4-Fluoro-benzyl)-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;-   2-Cyclopentyl-7-methyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;-   2-Cyclopentyl-4-(4-methoxy-phenyl)-7-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;-   2-Benzyl-7-methyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine;-   2-Isopropyl-4-p-tolyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepine    hydrochloride;-   2-Benzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine    hydrochloride;-   2-Benzyl-4-p-tolyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine    hydrochloride;-   2-Benzyl-4-phenyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;-   2-Benzyl-4-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine;-   2-Isopropyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine    hydrochloride; and-   {2-[2-tert-Butyl-6-(4-fluoro-phenyl)-pyrimidin-4-yl]-ethyl}-dimethyl-amine.

Additional preferred 5-HT7 antagonist compounds include:

-   (R)-3-[2-[2-(4-Methylpiperidin-1-yl)ethyl]pyrrolidine-1-sulfonyl]phenol    (SB269970);-   (R)-3,N-Dimethyl-N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]benzene    sulfonamide (SB258719);-   R-(+)-1-(toluene-3-sulfonyl)-2-[2-(4-methylpiperidin-1-yl)ethyl]-pyrrolidine;    (SB258741);-   LY-215840;-   2a-[4-4-phenyl-1,2,3,6-tetrahydropyridyl])-2a,3,4,5-tetrahydrobenzo[ed]-indol[(1H)-1    (DR 4004);-   Ensaculin (Schwabe);-   S 23751 (Servier/Universite D'Orleans);-   Zopetine (Fujisawa/Knoll/Klinge Pharma GmbH);-   SB248709 (GlaxoSmithKline); and-   BTS 79018 (Knoll/Abbott).

Preferably, 5-HT7 receptor antagonists are those that possess activityagainst the 5-HT7 receptor of less than or equal to 100 nM.

Exemplary SRIs that may be used in the methods and compositions of theinvention are selected from the various compounds known in the arthaving SRI activity or as suitably modulating the activity of theserotonin transporter (SERT) receptor, such as those generically orspecifically described in described in: International Publication Nos.WO 2006/016262, WO 2005/056056, WO 2005/030132, and WO 01/41766; U.S.Pat. Nos. 4,536,518, 4,314,081, 4,136,193, and 4,007,196; US PatentApplication Publication No. 2005/0288355; U.S. patent application Ser.No. 11/424,751, filed Jun. 16, 2006, application Ser. No. 11/424,734,filed Jun. 16, 2006, and application Ser. No. 11/300,880, filed Dec. 15,2005; and U.S. Provisional Application Nos. 60/806,169, filed Jun. 29,2006, 60/806,167, filed Jun. 29, 2006, and 60/806,165, filed Jun. 29,2006; the disclosures of which are incorporated by reference herein.Especially preferred SRIs include SSRIs such as dapoxetine,1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile(citalopram), escitalopram,N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-propan-1-amine(fluoxetine), fluvoxamine,(1S)-cis-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine(sertraline),(3S-trans)-3-((1,3-Benzodioxol-5-yloxy)methyl)-4-(4-fluorophenyl)-piperidine(paroxetine), venlafaxine, vilazodone, duloxetine, nefazodone,imipramine, femoxetine, clomipramine, cericlamine, clovoxamine,cyanodothiepin, ifoxetine, indalpine, indeloxazine, litoxetine,milnacipran, tametraline, viqualine, and zimeldine, and theirpharmaceutically acceptable salts. In one particularly preferredembodiment, the SRI is citalopram, sertraline, paroxetine, fluoxetine,or dapoxetine, or a pharmaceutically acceptable salt thereof.

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base compound that is non-toxic, biologically tolerable, orotherwise biologically suitable for administration to the subject. See,generally, Berge, et al., “Pharmaceutical Salts”, J. Pharm. Sci., 1977,66:1-19. Exemplary pharmaceutically acceptable salts include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates,methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates.

Although the 5-HT7 receptor antagonist agent and an SRI agent used inaccordance with the invention are preferably selective for or specificto a 5-HT7 receptor or a SERT, respectively, either one or both of theagents may also bind to or inhibit another receptor. Thus, one or moreof the 5-HT7 receptor antagonist agents or SRI agents may be dualinhibitors. For example, a dual 5-HT2 receptor antagonist/5-HT7 receptorantagonist (see, e.g., US Patent Application Publication No. US2005/0119295 and International Publication No. WO 2005/040169) may beused in combination with an SRI. Similarly, a suitable dual histamine H3receptor/SERT inhibitor or SRI (see, e.g., International Publication No.WO 2006/066197, U.S. patent application Ser. No. 11/300,880, filed Dec.15, 2005, application Ser. No. 11/424,734, filed Jun. 16, 2006, andapplication Ser. No. 11/424,751, filed Jun. 16, 2006, InternationalPatent Application No. PCT/US2006/023552, filed Jun. 12, 2006, and U.S.Provisional Patent Application Nos. 60/806,165, filed Jun. 29, 2006,60/806,167, filed Jun. 29, 2006, and 60/806,169, filed Jun. 29, 2006,may be used in combination with a 5-HT7 receptor antagonist.

The present invention also relates to pharmaceutical compositions fortreating a serotonin-mediated disease or condition comprising: a) anamount of a 5-HT7 receptor antagonist and an amount of an SRI; and b) apharmaceutically acceptable excipient. In preferred embodiments, theamount of the 5-HT7 receptor antagonist is a potentiating orameliorative amount. In further preferred embodiments, the amount of theSRI is a potentiating or ameliorative amount. In a particularlypreferred embodiment, the composition comprises an effective amount ofan SSRI, preferably citalopram, and an ameliorative amount of a 5-HT7receptor antagonist sufficient to ameliorate the sleep-fragmentationinduction effect of the SSRI.

Optionally, the 5-HT7 receptor antagonist and SRI may be combined withadditional active ingredients. The additional active ingredients may beco-administered separately with the 5-HT7 receptor antagonist and SRIagents of the invention (i.e., each in its own unit dosage form), or oneor more of the active ingredients may be delivered together in a singlecomposition or unit dosage form containing the agents in apharmaceutical composition according to the invention.

In one embodiment, the 5-HT7 receptor antagonist and SRI arecoadministered in separate pharmaceutical formulations. In a preferredembodiment, the two agents are formulated together into a singlepharmaceutical composition. In such pharmaceutical compositions of theinvention, the 5-HT7 receptor antagonist and SRI, with optional activeingredients, are combined. In a general aspect, a pharmaceuticalcomposition of the invention therefore comprises: an effective orcomplementary amount of at least one 5-HT7 receptor antagonist agent andan effective or complementary amount of at least one SRI agent, suchamounts of agents together providing an effective combined amount; alongwith a pharmaceutically acceptable excipient.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluent to facilitate administration of a pharmaceutical agent and thatis compatible therewith. Examples of excipients include calciumcarbonate, calcium phosphate, various sugars and types of starch,cellulose derivatives, gelatin, vegetable oils, and polyethyleneglycols.

Delivery forms of the pharmaceutical compositions containing one or moredosage units of the pharmaceutical agents may be prepared using suitablepharmaceutical excipients and compounding techniques known or thatbecome available to those skilled in the art. The compositions may beadministered in the inventive methods by a suitable route of delivery,e.g., oral, parenteral, rectal, topical, or ocular routes, or byinhalation. Additionally, dosage forms may be prepared as immediate-,timed-, controlled-, or extended-release formulations.

The preparation may be in the form of tablets, capsules, sachets,dragees, powders, granules, lozenges, powders for reconstitution, liquidpreparations, or suppositories. Preferably, the compositions areformulated for intravenous infusion, topical administration, or oraladministration.

For oral administration, the compounds can be delivered separately ortogether in the form of tablets or capsules, or as a solution, emulsion,or suspension. Oral tablets may include one or both of the agents andany other active ingredients mixed with compatible pharmaceuticallyacceptable excipients such as diluents, disintegrating agents, bindingagents, lubricating agents, sweetening agents, flavoring agents,coloring agents and preservative agents. Suitable inert fillers includesodium and calcium carbonate, sodium and calcium phosphate, lactose,starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol,sorbitol, and the like. Exemplary liquid oral excipients includeethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone(PVP), sodium starch glycolate, microcrystalline cellulose, and alginicacid are exemplary disintegrating agents. Binding agents may includestarch and gelatin. The lubricating agent, if present, may be magnesiumstearate, stearic acid or talc. If desired, the tablets may be coatedwith a material such as glyceryl monostearate or glyceryl distearate todelay absorption in the gastrointestinal tract, or may be coated with anenteric coating.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, active ingredient may be mixed with asolid, semi-solid, or liquid diluent. Soft gelatin capsules may beprepared by mixing the active ingredient with water, an oil such aspeanut oil or olive oil, liquid paraffin, a mixture of mono anddi-glycerides of short chain fatty acids, polyethylene glycol 400, orpropylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions or syrups or may be lyophilized or presented as adry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may optionally contain:pharmaceutically-acceptable excipients such as suspending agents (forexample, sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (for example, almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water;preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbicacid); wetting agents such as lecithin; and, if desired, flavoring orcoloring agents.

The active agents may also be administered by non-oral routes. Forexample, the compositions may be formulated for rectal administration asa suppository. For parenteral use, including intravenous, intramuscular,intraperitoneal, or subcutaneous routes, the agents of the invention maybe provided in sterile aqueous solutions or suspensions, buffered to anappropriate pH and isotonicity or in parenterally acceptable oil.Suitable aqueous vehicles include Ringer's solution and isotonic sodiumchloride. Such forms may be presented in unit-dose form such as ampoulesor disposable injection devices, in multi-dose forms such as vials fromwhich the appropriate dose may be withdrawn, or in a solid form orpre-concentrate that can be used to prepare an injectable formulation.Illustrative infusion doses range from about 1 to 1000 μg/kg/minute ofagent, admixed with a pharmaceutical carrier over a period ranging fromseveral minutes to several days.

For topical administration, the agents may be mixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle. Another mode of administering the agents of theinvention may utilize a patch formulation to affect transdermaldelivery.

The combination of 5-HT7 receptor antagonist and SRI agents mayalternatively be administered by inhalation, via nasal or oral route,e.g., in a spray formulation also containing a suitable carrier.

Various formulations for delivering the combination of 5-HT7 receptorantagonist and SRI in accordance with the invention, either in separatecompositions or a single composition, may be routinely developed in viewof guidance in the art. See, e.g., U.S. Pat. Nos. 4,576,604, 4,673,405,4,857,330, 5,997,905, and 6,149,943; US Patent Application PublicationNo. 2005/0232986; and International Publication Nos. WO 2003/035070 andWO 2000/032173.

Certain aspects, features, or advantages of the invention or exemplaryor preferred embodiments are illustrated by the following examples.

EXAMPLES

Animals. All studies involving live animals were carried out inaccordance with the Guide for the Care and Use of Laboratory Animals asadopted and promulgated by the US National Institutes of Health. Tailsuspension test and locomotor activity measurements were performed inmale C57BL/6J mice (Jackson Laboratories) weighing 22-30 grams.Microdialysis blood brain barrier penetration and EEG/EMG experimentswere performed in male Sprague-Dawley rats (Charles River, Wilmington,Mass.) weighing 280-320 grams (microdialysis) or 400-500 grams(EEG/EMG). Animals were allowed to acclimate for at least seven daysafter receipt before experiments were performed. Animals weregroup-housed in accordance with institutional standards, provided foodand water ad libitum, and were maintained on a 12-hour light dark (cycle(lights on: 6:00 to 18:00).

Agents.(R)-3-[2-[2-(4-Methylpiperidin-1-yl)ethyl]pyrrolidine-1-sulfonyl]phenolhydrochloride (SB269970) and1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile,HBr salt (citalopram) were purchased from Sigma (Saint Louis, Mo.).1-Benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene(Compound A) was prepared (see WO 2005/040169 and U.S. PatentApplication Publication No. US 2005/0119295). Doses of agents areexpressed as their free base.

Tail suspension test. SB269970, citalopram, Compound A,co-administration of SB269970 and citalopram, or co-administration ofCompound A and citalopram were each tested at the intraperitoneal (i.p.)doses described below and in the figures. A vehicle control (5%dextrose) and a positive control (citalopram, 5 mg/kg i.p.) wereincluded in experiments indicated. All compounds were formulated in 5%dextrose. Dilutions of compound stock solutions were prepared withvehicle. All doses were randomized and administered at 10 mL/kg, i.p.Mice were dosed thirty minutes prior to testing. Mice were prepared foruse in tail suspension tests by adhering a piece of tape to the uppermiddle of each animal's tail, creating a flap with the overlap of tape.One strand of a size 0 polyester suture with an attached needle was tiedto a previously calibrated force transducer (AD Instruments MLT500/D).The needle end of the suture hung down from the force transducer, andwas inserted through the tape flap of each animal. All mice were hungface-down from the force transducer in this manner for six minutes.During testing a Power Lab (AD Instruments, Colorado Springs, Colo.)recorded the data from the force transducer via a bridge amplifier. Thedata were accessible using Chart 4 software (AD Instruments, ColoradoSprings, Colo.). Time spent struggling and time spent immobile weredifferentiated by hand-scoring of the force-versus-time trace using theChart 4 software. The time spent immobile was totaled for the last fourminutes of the six-minute test for each animal, averaged for each dosegroup, and then compared. Data were graphed and statistics werecalculated using Prism software (GraphPad, San Diego, Calif.). Data arepresented as the mean±SEM and evaluated by one-way analysis of variancefollowed by Bonferroni's multiple comparison test. Differences wereconsidered significant at p<0.05

Locomotor activity. SB269970 (10 mg/kg i.p.), citalopram (1 mg/kg i.p.),Compound A (1 mg/kg i.p.), co-administration of SB269970 (10 mg/kg i.p.)and citalopram (1 mg/kg i.p.), or co-administration Compound A (1 mg/kgi.p.) and citalopram (1 mg/kg i.p.) were tested. Drugs were formulatedin 5% dextrose. Animals in the vehicle group were injected with 5%dextrose. Locomotor activity was measured with the MotorMonitor System(Hamilton Kinder software© 2000) by placing an animal's home cage insidea metal cage rack that contained photocell arrays. Basic movements weredefined as movements that broke a beam in an X-Y plane. Photodetectorswere connected to an IBM computer and test session data wereelectronically recorded. Each photocell beam interruption constitutedone activity count, and total counts per 10-minute period were tabulatedfor a 180-minute test session. Each test session consisted of a one-hourhabituation period, followed by a two-hour observation period, duringwhich time the effect of the agents on locomotor activity was assessed.One-way measures analysis of variance (ANOVA) was conducted to determinea treatment effect. Spontaneous locomotor activity data were expressedas mean±SEM and plotted in 5-minute bins and one-way ANOVA was conductedon the first 60 minutes of each session. The level of significance wasp<0.05.

Microdialysis. For probe implantation, each rat was given a 0.05 mLsubcutaneous (s.c.) injection of Buprenex (buprenorphine hydrochloride)at 0.06 mg/kg, five minutes prior to anesthesia. Animals wereanesthetized with an Isoflurane/air mixture and stereotaxicallyimplanted with a guide cannula (Eicom) in the prefrontal cortex (incisorbar, −3.5 mm, +3.2 mm anterior, 0.8 mm lateral and 1 mm ventral toBregma (Paxinos and Watson, 1997)). The guide cannula was secured inplace with skull screws and dental cement. Probe-implanted animals wereallowed at least four days to recover from surgery prior toexperimentation. Dialysis experiments were conducted between 8:00 a.m.and 3:00 p.m. in a controlled environment. Animals remained in theirhome cage throughout each study.

Doses of SB269970, Compound A, SB269970 and citalopram, or Compound Aand citalopram were given subcutaneously. All compounds were formulatedin 5% Pharmasolve and 95% dextrose. Dialysis probes (4-millimeter activemembrane length; Eicom) were perfused with artificial cerebral spinalfluid (147 mM NaCl, 4 mM KCl, 0.85 mM MgCl₂, 2.3 mM CaCl₂, pH 7.4) at aflow rate of 1 μL/min and implanted the afternoon prior to samplecollection. Each probe was connected via FEP tubing to a liquid swivel(QM; Instech) mounted on a counter-balance arm. The following morning,two hours of baseline samples were collected into a 96-well plate(Sarstedt, 96-well multiply PCR) via a four-channel fraction collector(Eicom). Samples were collected every 30 minutes for 6 hours in the96-well plates, which contained 7.5 μL of an antioxidant solution (0.1 Macetic acid, 1 mM oxalic acid and 3 mM L-cysteine in sterile water)maintained at 4° C. Samples were analyzed immediately following eachexperiment.

Dialysis samples were analyzed for 5-hydroxytryptamine (5-HT), dopamine(DA), and norepinephrine (NE) by high-performance liquid chromatographywith electrochemical detection (HPLC-ECD). Separation of DA was achievedusing an Eicompak PP-ODS column (4.6 mm (interior diameter)×30 mm;Eicom) with the potential of the graphite electrode set to +400 mVagainst a Ag/AgCl reference electrode. The mobile phase consisted of 100mM sodium phosphate buffer (pH 6.0), 500 mg/L decanesulfonic acid, 50mg/L EDTA, and 1% (vol/vol) methanol. NE detection was achieved byHPLC-ECD using an Eicompak CA-50DS column (2.1 mm (interiordiameter)×150 mm; Eicom) with the potential of the graphite electrode(Eicom) set to +450 mV against an Ag/AgCl reference electrode. Themobile phase consisted of 100 mM sodium phosphate buffer (pH 6.0), 400mg/L octanesulphonic acid, 50 mg/L EDTA, and 5% (vol/vol) methanol. Theconcentration for each sample was calculated from the peak area of thechromatographic signal and the slope from the corresponding standardcurve. The percent change from baseline values was calculated from themean basal value of each neurotransmitter for each animal, and presentedas mean±SEM. The area under the curve (AUC) values were calculated bythe summation of the difference between each neurotransmitter post-agentadministration and the mean percent of basal release value (100%). Forstatistical analysis, a one-way analysis of variance (ANOVA) andNewman-Keuels multiple conversion post hoc test was performed. Data wasgraphed and statistics were calculated using Prism software (GraphPad,San Diego, Calif.).

Pharmacokinetics and bioanalysis. Rats received an s.c. dose ofcitalopram (3 mg/kg) alone, citalopram (3 mg/kg) and SB269970 (10mg/kg), or citalopram (3 mg/kg) and Compound A (1 mg/kg). Dosing wasfollowed by blood sampling via cardiac puncture over a time course.Brains were removed from animals and homogenized for LC/MS-MS analysis.

All blood samples were deproteinized by making 1:4 dilutions of eachsample with acetonitrile (one part sample:four parts acetonitrile) andmixing vigorously. These samples were incubated for five minutes, andthen centrifuged at 14,000 rpm in a microcentrifuge for four minutes.The supernatant was recovered in auto-sampler vials and diluted 1:1 withsterile water. Samples were analyzed by LC-MS/MS. A Vydac SP C18 2.1×50mm analytical column was used for separation.

Independent Effects: 5-HT7 Receptor Antagonism by SB269970 and CompoundA on Mouse Behavior in the Setting of the Tail Suspension Test

The tail suspension test is a behavioral test in mice that is employedto characterize clinical efficacy of certain psychotropic agents,including antidepressants (Steru et al., Prog. Neuropsychopharmacol. &Biol. Psychiatry, Vol. 11(6), pp. 659-671 (1987). Animals administeredan antidepressant drug and subjected to the tail suspension testtypically display an increase in struggling and a decrease in the amountof time that the animal spends immobile during the test, compared tovehicle treated animals. Thus, agents may be administered to animals inthe setting of the tail suspension test in order to assess theirantidepressant qualities by measuring these parameters. Accordingly,either of the 5-HT7 receptor antagonists SB269970 or Compound A, eitheralone or together with the SSRI citalopram, was administered toindependent groups of mice, and the effects on struggling time andimmobilization time were measured in the setting of the tail suspensiontest for each group.

As depicted in FIG. 1A, administration of 3, 10, and 30 mg/kg ofSB269970 decreased the immobility time of mice in the tail suspensiontest treated mice by 43%, 59% and 79%, respectively, compared to vehicle(p<0.05, p<0.001, and p<0.001, respectively). These efficacies weresimilar to the efficacy observed with administration of 5 mg/kg i.p.citalopram used as a positive control (immobility time decreased by 51%vs. vehicle, p<0.01). As depicted in FIG. 1B, administration of 0.3,0.5, and 1 mg/kg of Compound A decreased the immobility time of treatedmice by 31%, 39%, and 51%, respectively, compared to vehicle (p<0.05,p<0.01, and p<0.01, respectively, with greatest efficacy observed at the1 mg/kg dose.

Collectively, these results reflect that each of the 5-HT7 receptorantagonists tested, SB269970 and Compound A, exerts an antidepressanteffect on treated animals when administered alone relative to vehiclecontrols, and that Compound A appears to exhibit a greater potency as anantidepressant than SB269970.

Combined Effects of 5-HT7 Receptor Antagonism and Serotonin ReuptakeInhibition by SB269970 or Compound A with Citalopram Co-Administration

In an effort to investigate whether a combined effect elicited by 5-HT7receptor antagonism and serotonin reuptake inhibition might be observedin the setting of the tail suspension test, SB269970 and Compound A wereindependently co-administered with citalopram in the setting of the tailsuspension test. When citalopram was administered alone i.p. at doses of3, 5 and 10 mg/kg, immobility time was significantly decreased comparedto administration of vehicle alone (35%, 54%, and 74% decrease, (p<0.01,p<0.001, and p<0.001), respectively; see FIGS. 2A and 2B).Co-administration of SB269970 (10 mg/kg i.p.) and citalopram at 1, 3, 5and 10 mg/kg i.p. each significantly decreased immobility time relativeto vehicle alone by 55%, 58%, 68%, and 86%, respectively (p<0.001 forall doses; see FIG. 2A). Co-administration of 1 mg/kg and 3 mg/kg dosesof citalopram with SB269970 at 10 mg/kg i.p. each significantly enhancedthe effect of citalopram administration alone (55% vs. 20% (p<0.001) and58% vs. 35% (p<0.05), respectively; see FIG. 2A). Co-administration of1, 3, 5, and 10 mg/kg doses of citalopram with Compound A at 1 mg/kgi.p.—each a ten-fold lower dosage than the respective dosage used forSB269970—each decreased immobility time relative to vehicle alone by49%%, 70% %, 80%%, and 84%%, respectively (p<0.001 for all doses; seeFIG. 2B). The effect of co-administration with Compound A was mostpronounced at the 1 mg/kg, 3 mg/kg, and 5 mg/ml citalopram dosesrelative to the effect of citalopram administration alone (49% vs. 21%(p<0.001), 70% vs. 36% (p<0.001), and 80% vs. 54% (p<0.001),respectively; see FIG. 2B).

None of SB269970 (10 mg/kg i.p), Compound A (1 mg/kg i.p), or citalopram(1 mg/kg i.p.) significantly altered locomoter activity of treated micewithin the first 30 minutes subsequent to administration of the compoundcompared to that observed in vehicle-treated mice throughout the sametime period (FIGS. 3A and 3B, respectively. In each figure, compare lane1 vs. lane 4 and lane 2 vs. lane 4, respectively (p>0.05 for allcomparisons)). Similarly, neither co-administration of SB269970 (10mg/kg i.p) nor Compound A (1 mg/kg i.p.) with citalopram (1 mg/kg i.p.)significantly altered locomotor activity of treated mice, relative tocitalopram alone or to vehicle control, within the first 30 minutessubsequent to administration of the compounds (FIGS. 3A and 3B,respectively. In each figure, compare lane 3 vs. lane 2 and lane 3 vs.lane 4, respectively (p>0.05 for all comparisons)). Collectively, theseresults reflect that co-administration of either SB269970 or Compound Awith citalopram significantly potentiates the antidepressant effectsobserved with citalopram in the setting of the tail suspension test.While the potentiation efficacy was found to be dose-dependent withrespect to citalopram dosage in both co-administration regimens tested,Compound A was found to be roughly ten times as potent as SB269970, inthat approximately one-tenth the amount of Compound A relative to theamount of SB269970 was sufficient to potentiate to a similar magnitudethe effect of citalopram alone on immobility time in the setting of thetail suspension test.

Effect of Combination of Sub-Efficacious Doses of Citalopram and EitherSB269970 or Compound A

The previous examples demonstrate that the co-administration ofefficacious doses of a 5-HT7 receptor antagonist and an SSRI can producea greater effect on immobility time than that observed when anefficacious dose of either substance is administered alone. In an effortto determine whether co-administration of sub-efficacious doses of a5-HT7 receptor antagonist and an SSRI might yield an efficacious result,sub-efficacious doses of either citalopram or SB269970 wereco-administered with sub-efficacious doses of citalopram to mice, whowere then subjected to the tail suspension test. As reflected in FIG.4A, neither citalopram (1 mg/kg i.p.) nor SB269970 (1 mg/kg i.p.)significantly altered immobility time compared to vehicle treated mice(p>0.05). In contrast, co-administration of these sub-efficacious dosesof citalopram (1 mg/kg i.p.) and SB269970 (1 mg/kg i.p.) significantlydecreased the immobility time compared to that observed with vehiclealone (p<0.001; FIG. 4A). Similarly, citalopram (1 mg/kg i.p.) andCompound A, when administered alone at sub-efficacious doses (0.3 mg/kgi.p. and 0.1 mg/kg i.p., respectively) each only modestly decreasedimmobility times; however, when both citalopram and Compound A wereco-administered at these sub-efficacious doses, a significant decreasein immobility time was observed compared to that observed with vehiclealone (FIG. 4B).

Effect of 5-HT7 Receptor Antagonism and Serotonin Reuptake Inhibition onPrefrontal Cortical Levels of 5-hydroxytryptamine

In order to determine whether the potentiating effect ofco-administration a 5-HT7 receptor antagonist with an SSRI might berelated to an increase in extracellular cortical 5-hydroxytryptamine(5-HT) levels, in vivo microdialysis experiments were performed on miceadministered either citalopram, SB269970, Compound A, or co-administeredcitalopram with either SB269970 or Compound A. Doses of 10 mg/kgSB269970, 1 mg/kg Compound A, and 3 mg/kg citalopram, which were eachefficacious when administered alone in tail suspension tests; see e.g.,FIGS. 1A-1B) were selected for initial microdialysis studies, and levelsof 5-hydroxytryptamine (5-HT), dopamine (DA), and norepinephrine (NE)were followed after dosing. Basal levels of 5-HT, DA, and NE indialysate from the frontal cortex (without adjusting for probe recovery)was 0.046±0.002 pg/10 μL (n=30), 0.12±0.008 pg/10 μL (n=30) and0.215±0.007 pg/10 μL (n=30), respectively. Whereas neitheradministration of SB269970 (10 mg/kg s.c.) alone nor Compound A (1 mg/kgs.c.) alone increased extracellular 5-HT concentration compared tovehicle, administration of citalopram (3 mg/kg s.c.) alone significantlyincreased the extracellular concentration of 5-HT compared to vehicle(FIG. 5A and FIG. 5C, respectively), similar to previous reports (seee.g., Bymaster et al., Psychopharmacology (Berl), Vol. 160(4), pp.353-361 (2002)). Extracelluar 5-HT concentration was significantlyincreased upon co-administration of either SB269970 (FIG. 5A) orCompound A (FIG. 5C) relative to 5-HT concentration observed uponcitalopram administration alone. Area-under-the-curve (AUC) analysis ofthe data presented in FIGS. 5A and 5C further reflected the significanceof the potentiating effect co-administration of citalopram and eitherSB269970 (FIG. 5B) or Compound A (FIG. 5D).

Additional experiments were performed using a sub-efficacious dose ofcitalopram (0.05 mg/kg s.c.), which did not significantly increaseextracellular concentration of 5-HT (FIGS. 6A and 6C) in combinationwith either SB269970 (10 mg/kg s.c.) or Compound A (1 mg/kg s.c.).Whereas the sub-efficacious citalopram dose did not significantlyincrease extracellular 5-HT concentrations, co-administration of 0.05mg/kg citalopram with either 10 mg/mL SB269970 or 1 mg/mL Compound Aresulted in a significant increase in extracellular 5-HT concentrationrelative to 5-HT concentration observed with citalopram administrationalone (FIG. 6A and FIG. 6C, respectively). AUC analysis of the datapresented in FIGS. 6A and 6C further reflected the significance of thepotentiating effect of co-administration of citalopram and eitherSB269970 (FIG. 6B) or Compound A (FIG. 6D).

None of citalopram (0.05 or 3 mg/kg s.c.), SB269970 (10 mg/kg s.c.),Compound A (1 mg/kg s.c.), co-administration of citalopram (0.05 or 3mg/kg s.c.) and SB269970 (10 mg/kg s.c.), or co-administration ofcitalopram (0.05 or 3 mg/kg s.c.) and Compound A (1 mg/kg s.c.) inducedsignificant change in extracellular concentrations of DA or NE.

Effect of SB269970 on Citalopram Blood Brain Barrier Penetration andPharmacokinetics Parameters

Citalopram plasma and brain concentrations were determined followings.c. dosing of citalopram alone (3 mg/kg) or co-administration ofcitalopram (3 mg/kg) and SB269970 (10 mg/kg). Co-administration ofSB269970 did not affect citalopram plasma or brain concentration, asreflected in FIGS. 7A and 7B, respectively.

Analysis of Sleep/Wake States in Rats Following the Co-Administration ofCitalopram and the 5-HT₇ Antagonist Compound A or SB269970

The response to administration of the selective serotonin reuptakeinhibitor citalopram in combination with the Compound A or SB269970 onsleep/wake states was analyzed using a rat telemetric in vivo system.For the determination of EEG/EMG waveforms, two stainless steel screwelectrodes for electroencephalogram (EEG) (frontal and parietal cortex)and wire electrodes electromyogram (EMG) (dorsal neck muscles) wereimplanted in each animal under isofluorane anesthesia. Electrodes wereconnected to a sterile 2-channel telemetric device (Data SciencesTL10M3-F50-EET) that had been implanted in the intraperitoneal cavity.The animals were allowed to recover for two weeks following surgery andthen moved to their designated housing/procedure room to allow foradaptation to the recording chamber and environment. On the designatedday the animals were to receive vehicle or compound administration,telemetric devices were activated in each animal ten minutes beforeinjection. EEG/EMG traces were recorded on an IBM PC-compatible computerusing Dataquest A.R.T software (Data Sciences, Inc.) at a sampling rateof 100 Hz.

At two hours after light onset (during the rodent sleep period), maleSprague-Dawley rats (n=9) were initially dosed subcutaneously withvehicle or Compound A at 0.3 mg/kg or SB269970 at 10 mg/kg. Uponcompletion of this first dose, animals were dosed with either citalopram(1 mg/kg) or vehicle. EEG/EMG signals were recorded for ten hoursfollowing administration of the test reagents and vigilant state (wake,NREM, or REM) was assigned in 10-second epochs by visual inspection.Quantitative analysis of EEG activity was performed by spectral analysisusing Fast Fourier Transformation. Utilizing the computer programSleepSign (Kissei, Inc.), consecutive EEG/EMG recordings were dividedinto 10-second epochs. Vigilance states were visually assigned to theseindividual epochs using the conventional criteria for wake (less regularlow amplitude EEG, EMG activation); non-rapid eye movement (NREM) sleep(high-amplitude EEG waves with predominant frequency in the delta range(0.5-5 Hz) and lack of body movement; rapid eye movement (REM) sleep(stable low amplitude EEG, dominance of theta activity (5.1-8 Hzfrequency range), with general EMG atonia). For the quantitativeanalysis of the EEG signal, power spectra were calculated for eachscored 10-second epoch, which was divided into five 2-second intervalsand then subjected to a fast Fourier transformation (FFT) for thefrequency range of 0.5-30.0 Hz. Those epochs that contained EEGartifacts were excluded from the FFT analyses. The resulting powerdensity spectra were divided into five predetermined frequency bands:delta (0.5-5 Hz), theta (5.1-8 Hz), alpha (8.1-12 Hz), sigma (12.1-14Hz), and beta (14.1-30 Hz). Subsequently, power spectra were averagedover all the epochs in each frequency band separately. After scoring theEEG/EMG traces, analysis and compilation of the raw data files wasexecuted by a proprietary sleep analysis program. Using a fullycustomizable computer script in conjunction with the software program R,several parameters relating to the architecture (time spent in wake,NREM, or REM), continuity and consolidation of the sleep/wake cycle(i.e., bout analysis) were evaluated. A bout was defined as at least twoconsecutive epochs, 20 s, of wake, NREM, or REM. Micro-arousals fromsleep (NREM or REM sleep bout interrupted by a 10-s epoch of wake) andawakenings from NREM (number of transitions between a NREM bout to about of wake) were also measured. Spectral analysis of the EEG wasperformed in the states of wake, NREM, and REM sleep, respectively.Results were averaged and expressed as mean±S.E.M. in defined timeintervals. To determine if differences were significant at a giveninterval, either a one-way ANOVA with Neuman-Keuls post hoc analysis ortwo-way repeated measures ANOVA followed by a Bonferroni post hoc testwas executed. Differences were determined to be significant if p<0.05.The results are summarized in Tables 1 and 2 below.

TABLE 1 NREM and REM sleep latencies following co-administration ofcitalopram (1 mg/kg) and Compound A (0.3 mg/kg) (A) or SB269970 (B) (10mg/kg) (n = 9.) A) Vehicle + Compound Vehicle + Compound Vehicle A +Vehicle Citalopram A + Citalopram NREM 28.9 ± 3.5 23.0 ± 3.0  30.9 ±3.8  28.9 ± 1.7   REM 55.4 ± 5.8 67.1 ± 4.2^(#) 94.3 ± 11.1* 153.9 ±13.2*** *P < 0.05 v. Vehicle + Vehicle ***P < 0.001 v. Vehicle +Vehicle, Compound A + Vehicle, and Vehicle + Citalopram ^(#)P < 0.05 v.Vehicle + Citalopram B) Vehicle + SB269970 + Vehicle + SB269970 +Vehicle Vehicle Citalopram Citalopram NREM 28.9 ± 3.5 34.5 ± 4.2 30.9 ±3.8  33.0 ± 4.6  REM 55.4 ± 5.8 78.7 ± 8.0 94.3 ± 11.1* 158.7 ± 12.3***P < 0.05 v. Vehicle + Vehicle **P < 0.001 v. Vehicle + Vehicle,SB269970 + Vehicle, and Vehicle + Citalopram

TABLE 2 REM bout analysis following co-administration of citalopram (1mg/kg) and Compound A (0.3 mg/kg) (A) or SB269970 (B) (10 mg/kg) (n = 9)A) Vehicle + Compound Vehicle + Compound Vehicle A + Vehicle CitalopramA + Citalopram Number 37.8 ± 2.4 34.3 ± 1.4 35.1 ± 2.7 24.9 ± 1.5*** ofREM Bouts REM  1.8 ± 0.1  1.8 ± 0.1  1.7 ± 0.1 2.0 ± 0.1*  Bout Duration(Minutes) *P < 0.05 v. Vehicle + Citalopram ***P < 0.001 v. Vehicle +Vehicle, Compound A + Vehicle, and Vehicle + Citalopram B) Vehicle +SB269970 + Vehicle + SB269970 + Vehicle Vehicle Citalopram CitalopramNumber 37.8 ± 2.4 29.0 ± 1.5*^(,) ** 35.1 ± 2.7 23.0 ± 1.3*** of REMBouts REM  1.8 ± 0.1 2.0 ± 0.1    1.7 ± 0.1 2.1 ± 0.1*  Bout Duration(Minutes) *P < 0.05 v. SB269970 + Citalopram **P < 0.01 v. Vehicle +Vehicle and Vehicle + Citalopram ***P < 0.001 v. Vehicle + Vehicle andVehicle + Citalopram

Administration of citalopram, Compound A, or SB269970, either asstand-alone therapy or as a combination, did not influence the timespent awake (FIG. 8), the latency to NREM sleep (Table 1) or duration ofNREM sleep (FIG. 9), or the intensity of NREM sleep as indexed by theEEG spectral analysis in the delta frequency band (FIG. 10). Citalopramtreatment induced a significant increase in REM sleep latency, whereasthe 5-HT7 antagonists had no effect at the doses tested (Table 1). Thecombination of citalopram with Compound A or SB269970 significantlydelayed the onset of the first episode of REM sleep (˜60 and 65 minutes,respectively) as compared to citalopram alone (Table 1). In addition,the treatment with Compound A or SB269970 potentiated the decrease inREM sleep duration induced by citalopram (FIG. 11). This inhibitoryeffect on REM sleep duration was mainly due to a decrease in the numberof REM sleep bouts whereas the mean duration was slightly increased(Table 2). Interestingly, the administration of these two 5-HT7antagonists in combination with citalopram resulted in decreased sleepfragmentation as evidenced by a significant decrease in the number ofmicro-arousals (FIG. 12).

While the invention has been illustrated by reference to examples andpreferred embodiments, it is understood that the invention is intendedto be not limited by the foregoing detailed description, but defined bythe appended claims applying principles of patent law.

What is claimed is:
 1. A pharmaceutical composition comprising: (a) (i) a therapeutically effective amount of a 5-HT7 receptor antagonist, wherein said 5-HT7 receptor antagonist is selected from the group consisting of: (R)-3-[2-[2-(4-Methylpiperidin-1-yl)ethyl]pyrrolidine-1-sulfonyl]phenol; (R)-3,N-Dimethyl-N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]benzene sulfonamide; R-(+)-1-(toluene-3-sulfonyl)-2[2-(4-methylpiperidin-1-yl)ethyl]-pyrrolidine; LY-215840; 2a-[4-4-phenyl-1,2,3,6-tetrahydropyridyl])-2a,3,4,5-tetrahydrobenzo[ed]-indol[(iH)-1; Ensaculin; S 23751; Zopetine; SB248709; BTS 79018; and 1-Benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; and (ii) a therapeutically effective amount of a serotonin reuptake inhibitor, said amounts together providing an effective combined amount; and (b) a pharmaceutically acceptable excipient.
 2. A pharmaceutical composition according to claim 1, wherein the amount of said 5-HT7receptor antagonist is a complementary amount.
 3. A pharmaceutical composition according to claim 1, wherein the amount of said serotonin reuptake inhibitor is a complementary amount.
 4. A pharmaceutical composition according to claim 1, wherein said serotonin reuptake inhibitor is dapoxetine, citalopram, escitalopram, fluoxetine, fluvoxamine, sertraline, paroxetine, venlafaxine, vilazodone, duloxetine, nefazodone, imipramine, femoxetine, clomipramine, cericlamine, clovoxamine, cyanodothiepin, ifoxetine, indalpine, indeloxazine, litoxetine, milnacipran, tametraline, viqualine, or zimeldine, or a pharmaceutically acceptable salt thereof.
 5. A pharmaceutical composition according to claim 1, wherein said serotonin reuptake inhibitor is citalopram, sertraline, paroxetine, fluoxetine, or dapoxetine.
 6. A pharmaceutical composition according to claim 1, wherein said 5-HT7 receptor antagonist is 1-Benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene and said serotonin reuptake inhibitor is citalopram.
 7. A method of treating a subject suffering from or diagnosed with a serotonin-mediated disease or condition, comprising administering to a subject in need of such treatment: a therapeutically effective amount of a 5-HT7 receptor antagonist, wherein said 5-HT7 receptor antagonist is selected from the group consisting of: (R)-3-[2-[2-(4-Methylpiperidin-1-yl)ethyl]pyrrolidine-1-sulfonyl]phenol; (R)-3,N-Dimethyl-N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]benzene sulfonamide; R-(+)-1-(toluene-3-sulfonyl)-2-[2-(4-methylpiperidin-1-yl)ethyl]-pyrrolidine; LY-215840; 2a-[4-4-phenyl-1,2,3,6-tetrahydropyridyl])-2a,3,4,5-tetrahydrobenzo[ed]-indol[(iH)-1; Ensaculin; S 23751; Zopetine; SB248709; BTS 79018; and 1-Benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; and a therapeutically effective amount of a serotonin reuptake inhibitor, said amounts together providing an effective combined amount.
 8. A method according to claim 7, wherein the amount of said 5-HT7 receptor antagonist is a complementary amount.
 9. A method according to claim 7, wherein the amount of said serotonin reuptake inhibitor is a complementary amount.
 10. A method according to claim 7, wherein: said serotonin reuptake inhibitor is a selective serotonin reuptake inhibitor; the amount of said 5-HT7 receptor antagonist is an ameliorative amount; and said 5-HT7 receptor antagonist is selected from the group consisting of: (R)-3-[2-[2-(4-Methylpiperidin-1-yl)ethyl]pyrrolidine-1-sulfonyl]phenol; (R)-3,N-Dimethyl-N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]benzene sulfonamide; R-(+)-1-(toluene-3-sulfonyl)-2-[2-(4-methylpiperidin-1-yl)ethyl]-pyrrolidine; LY-215840; 2a-[4-4-phenyl-1,2,3,6-tetrahydropyridyl])-2a,3,4,5-tetrahydrobenzo[ed]-indol[(iH)-1; Ensaculin; S 23751; Zopetine; SB248709; BTS 79018; and 1-Benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; and pharmaceutically acceptable salts thereof.
 11. The method according to claim 7, wherein the disease or condition is selected from the group consisting of depression, anxiety, sleep or wake disturbances, and jet-lag.
 12. A method according to claim 7, wherein said disease or condition is depression or anxiety.
 13. A method according to claim 7, wherein said selective serotonin reuptake inhibitor is citalopram.
 14. A method according to claim 13, wherein said disease or condition is selected from the group consisting of depression, anxiety, sleep or wake disturbances, and jet-lag.
 15. A method according to claim 13, wherein said 5-HT7 receptor antagonist is 1-Benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene. 